Journal of Neuroscience,
Год журнала:
2021,
Номер
42(2), С. 166 - 182
Опубликована: Ноя. 22, 2021
The
K+-Cl-
cotransporter
KCC2,
encoded
by
the
Slc12a5
gene,
is
a
neuron-specific
chloride
extruder
that
tunes
strength
and
polarity
of
GABAA
receptor-mediated
transmission.
In
addition
to
its
canonical
ion
transport
function,
KCC2
also
regulates
spinogenesis
excitatory
synaptic
function
through
interaction
with
variety
molecular
partners.
enriched
in
vicinity
both
glutamatergic
GABAergic
synapses,
activity
which
turn
membrane
stability
function.
submembrane
actin
cytoskeleton
via
4.1N
known
control
anchoring
near
synapses
on
dendritic
spines.
However,
determinants
clustering
remain
unknown.
Here,
we
used
proteomics
identify
novel
interacting
proteins
adult
rat
neocortex.
We
identified
candidate
partners,
including
some
involved
neuronal
development
These
include
gephyrin,
main
scaffolding
molecule
at
synapses.
Gephyrin
endogenous
was
confirmed
immunoprecipitation
from
neocortical
extracts.
showed
gephyrin
stabilizes
plasmalemmal
promotes
hippocampal
neurons,
mostly
but
not
exclusively
thereby
controlling
KCC2-mediated
extrusion.
This
study
identifies
as
expression
cortical
neurons.SIGNIFICANCE
STATEMENT
Fast
inhibition
brain
mediated
chloride-permeable
receptors
(GABAARs)
therefore
relies
transmembrane
gradients.
these
gradients
are
primarily
maintained
K/Cl
KCC2.
Therefore,
understanding
mechanisms
crucial
understand
physiological
regulation
rescue
pathology.
depends
clustering,
underlying
describe
between
protein
inhibitory
show
controls
loss
compromises
Our
data
suggest
functional
units
comprising
GABAARs,
act
regulate
GABA
signaling.
Neuropharmacology,
Год журнала:
2021,
Номер
205, С. 108910 - 108910
Опубликована: Дек. 6, 2021
The
Na-K-2Cl
cotransporter
NKCC1
and
the
neuron-specific
K-Cl
KCC2
are
considered
attractive
CNS
drug
targets
because
altered
neuronal
chloride
regulation
consequent
effects
on
GABAergic
signaling
have
been
implicated
in
numerous
disorders.
While
modulators
not
yet
clinically
available,
loop
diuretic
bumetanide
has
used
clinical
studies
to
treat
brain
disorders
as
a
tool
for
inhibition
preclinical
models.
Bumetanide
is
known
anticonvulsant
neuroprotective
under
some
pathophysiological
conditions.
However,
shown
several
species
from
neonates
adults
(mice,
rats,
dogs,
by
extrapolation
humans),
at
low
doses
of
approved
diuresis,
this
negligible
access
into
CNS,
reaching
levels
that
much
lower
than
what
needed
inhibit
cells
within
parenchyma.
Several
discovery
strategies
over
last
∼15
years
develop
brain-permeant
compounds
that,
ideally,
should
be
selective
eliminate
diuresis
mediated
renal
NKCC2.
employed
improve
pharmacokinetic
pharmacodynamic
properties
blockers
include
evaluation
other
diuretics;
development
lipophilic
prodrugs
bumetanide;
side-chain
derivatives
unbiased
high-throughput
screening
approaches
based
large
chemical
compound
libraries.
main
outcomes
(1),
non-acidic
diuretics
such
azosemide
torasemide
may
advantages
inhibitors
vs.
(2),
achieve
significantly
higher
parent
activity;
(3),
novel
do
exhibit
any
functionally
relevant
improvement
accessibility
or
selectivity
(4)
discovered
resolve
inherent
problems
bumetanide,
but
achieved.
Thus,
further
research
optimize
design
inhibitors.
Another
major
challenge
identify
mechanisms
whereby
various
NKCC1-expressing
cellular
these
(e.g.,
neurons,
oligodendrocytes
astrocytes)
outside
parenchyma
blood-brain
barrier,
choroid
plexus,
endocrine
immune
system),
well
molecular
off-target
effects,
might
contribute
their
reported
therapeutic
adverse
effects.
Frontiers in Cellular Neuroscience,
Год журнала:
2022,
Номер
15
Опубликована: Янв. 5, 2022
The
construction
of
the
brain
relies
on
a
series
well-defined
genetically
and
experience-
or
activity
-dependent
mechanisms
which
allow
to
adapt
external
environment.
Disruption
these
processes
leads
neurological
psychiatric
disorders,
in
many
cases
are
manifest
already
early
postnatal
life.
GABA,
main
inhibitory
neurotransmitter
adult
is
one
major
players
assembly
formation
neuronal
circuits.
In
prenatal
immediate
period
acting
GABA
A
receptors,
depolarizes
excites
targeted
cells
via
an
outwardly
directed
flux
chloride.
this
way
it
activates
NMDA
receptors
voltage-dependent
calcium
channels
contributing,
through
intracellular
rise,
shape
establish,
new
synapses
elimination
others,
direction
-mediated
neurotransmission
(depolarizing
hyperpolarizing)
depends
levels
chloride
[Cl
−
]
i
,
turn
maintained
by
cation-chloride
importer
exporter
KCC2
NKCC1,
respectively.
Thus,
premature
hyperpolarizing
action
its
persistent
depolarizing
effect
beyond
period,
behavioral
deficits
associated
with
morphological
alterations
excitatory
(E)/inhibitory
(I)
imbalance
selective
areas.
aim
review
summarize
recent
data
concerning
functional
role
GABAergic
transmission
building
up
refining
circuits
development
dysfunction
neurodevelopmental
disorders
such
as
Autism
Spectrum
Disorders
(ASDs),
schizophrenia
epilepsy.
particular,
we
focus
novel
information
co-transporters
(CCC)
generate
cognitive
impairment
diseases.
We
discuss
also
possibility
re-establish
proper
balance
within
areas
CCC.
Frontiers in Synaptic Neuroscience,
Год журнала:
2022,
Номер
14
Опубликована: Май 19, 2022
Synaptic
plasticity
is
a
critical
process
that
regulates
neuronal
activity
by
allowing
neurons
to
adjust
their
synaptic
strength
in
response
changes
activity.
Despite
the
high
proximity
of
excitatory
glutamatergic
and
inhibitory
GABAergic
postsynaptic
zones
functional
integration
within
dendritic
regions,
concurrent
has
historically
been
underassessed.
Growing
evidence
for
pathological
disruptions
excitation
inhibition
(E/I)
balance
neurological
neurodevelopmental
disorders
indicates
need
an
improved,
more
"holistic"
understanding
interplay.
There
continues
be
long-standing
focus
on
persistent
strengthening
(excitatory
long-term
potentiation;
eLTP)
its
role
learning
memory,
although
importance
potentiation
(iLTP)
depression
(iLTD)
become
increasingly
apparent.
Emerging
further
points
dynamic
dialogue
between
synapses,
but
much
remains
understood
regarding
mechanisms
extent
this
exchange.
In
mini-review,
we
explore
calcium
signaling
crosstalk
play
regulating
excitability.
We
examine
current
knowledge
synapse
responses
perturbances
activity,
with
induced
short-term
pharmacological
treatments
which
act
either
enhance
or
reduce
excitability
via
ionotropic
receptor
regulation
culture.
To
delve
deeper
into
potential
crosstalk,
discuss
influence
key
regulatory
proteins,
including
kinases,
phosphatases,
structural/scaffolding
proteins.
Finally,
briefly
suggest
avenues
future
research
better
understand
synapses.
Physiological Reviews,
Год журнала:
2022,
Номер
103(2), С. 1095 - 1135
Опубликована: Окт. 27, 2022
Synaptic
inhibition
plays
a
crucial
role
in
regulating
neuronal
excitability,
which
is
the
foundation
of
nervous
system
function.
This
largely
mediated
by
neurotransmitters
GABA
and
glycine
that
activate
Cl
−
-permeable
ion
channels,
means
strength
depends
on
gradient
across
membrane.
In
neurons,
primarily
two
secondarily
active
cation-chloride
cotransporters
(CCCs),
NKCC1
KCC2.
CCC-mediated
regulation
critical
for
healthy
brain
function,
as
dysregulation
CCCs
has
emerged
key
mechanism
underlying
neurological
disorders
including
epilepsy,
neuropathic
pain,
autism
spectrum
disorder.
review
begins
with
an
overview
chloride
transporters
before
explaining
dependent
relationship
between
these
CCCs,
regulation,
inhibitory
synaptic
transmission.
We
then
discuss
evidence
how
can
be
regulated,
activity
their
protein
interactions,
underlie
plasticity.
For
readers
who
may
interested
conducting
experiments
we
have
included
section
techniques
estimating
recording
intracellular
,
advantages
limitations.
Although
focus
this
also
examine
regulated
glial
cells,
turn
regulate
excitability
through
tight
nonneuronal
cell
type
synapses.
Finally,
relatively
extensive
growing
literature
contributes
to
disorders.
Cell Death and Disease,
Год журнала:
2023,
Номер
14(1)
Опубликована: Янв. 6, 2023
Abstract
SLC12A5,
a
neuron-specific
potassium-chloride
co-transporter,
has
been
reported
to
promote
tumor
progression,
however,
the
underlying
mechanism
remains
unclear.
Here
we
report
that
SLC12A5
functions
as
an
oncogene
progression
and
castration
resistance
of
prostate
cancer
through
N6-methyladenosine
(m
6
A)
reader
YTHDC1
transcription
factor
HOXB13.
We
have
shown
level
was
increased
in
cancer,
comparison
its
normal
counterparts,
further
elevated
castration-resistant
(CRPC).
The
enhanced
expression
mRNA
associated
with
neuroendocrine
(NEPC)
poor
survival
cancer.
Furthermore,
demonstrated
promoted
development
addition
cell
proliferation
migration.
Interestingly,
detected
nucleus
formed
complex
nuclear
m
A
YTHDC1,
which
turn
upregulated
HOXB13
progression.
Therefore,
our
findings
reveal
how
cotransporter
promotes
provide
therapeutic
opportunity
for
apply
neurological
disorder
drug
inhibitors.
Cell Reports Medicine,
Год журнала:
2023,
Номер
4(3), С. 100957 - 100957
Опубликована: Март 1, 2023
Hyperpolarizing
GABAAR
currents,
the
unitary
events
that
underlie
synaptic
inhibition,
are
dependent
upon
efficient
Cl−
extrusion,
a
process
is
facilitated
by
neuronal
specific
K+/Cl−
co-transporter
KCC2.
Its
activity
also
determinant
of
anticonvulsant
efficacy
canonical
GABAAR-positive
allosteric:
benzodiazepines
(BDZs).
Compromised
KCC2
implicated
in
pathophysiology
status
epilepticus
(SE),
medical
emergency
rapidly
becomes
refractory
to
BDZ
(BDZ-RSE).
Here,
we
have
identified
small
molecules
directly
bind
and
activate
KCC2,
which
leads
reduced
accumulation
excitability.
activation
does
not
induce
any
overt
effects
on
behavior
but
prevents
development
terminates
ongoing
BDZ-RSE.
In
addition,
reduces
cell
death
following
Collectively,
these
findings
demonstrate
promising
strategy
terminate
BDZ-resistant
seizures
limit
associated
injury.